Injectable penicillin compositions



Patented July 19, 1949 UNITED STATES INJECTABLE PENICILLIN COMPOSITIONSStephen B. Binkley, Detroit, Mich, assignor to Parke, Davis &Company,il)etroit, Mich., a corporation of Michigan No Drawing.Application June 7, 1945;

Serial No. 598,205

6 Claims.

This invention relates to repository products and to methods forObtaining the same. More particularly, the invention relates tocompositions containing the antibiotic known as penicillin.

At the present time it is the practice to admin-' inster salts ofpenicillin by intramuscular injection using saline solution as a,vehicle. When pen-cillin is administered in this manner it is quicklyabsorbed and large quantities appear in the blood stream soon afterinjection. These high blood levels of penicillinrapidly disappear due tothe rapid excretion and destruction of the antibiotic. It is thereforenecessary to reinject penicillin at twoor three-hour intervals ifdetectable amounts are-to be maintained in the blood stream. In aneffort to overcome this rapid elimination of penicillin, diodrast (thechemical combination of 3,5-diiodo-4-pyridone- N-acetic acid anddiethanolamine which contains about 50% iodine) or p-aminohippuric acidhave been administered with penicillin to interfere with renal functionand'thus depress the excretion of penicillin [PIOC. Soc. Exp. Biol. andMed, 53, 30 (1943) and Science, 100, 107 (1944) This unnaturalphysiological method has many obvious disadvantages in addition to thefact that it is not particularly efiective in accomplishing its purposeof maintaining high blood levels of penicillin over long periods oftime.

Another method of maintaining blood levels of penicillin afterintramuscular injection which hasbeen proposed in the retarding of theabsorption of penicillin by placing an ice pack over the area ofinjection to limit the local circulation [(Science, 100,432 (1944) Thismethod does not appreciably delay the absorption of penicillin andis'very cumbersome and extremely uncomfortable.

More recently the use-of vegetable oils and beeswax-peanut oil mixtureshave been suggested as vehicles for penicillin because of theirslow rateof absorption [Science, 100, 412 94 and Science, 100, 196 (1944)]. Evenwhen using these slowly absorbed vehicles for penicillin it is necessaryto reinject penicillin every three or four hours to maintain adequatetherapeutic blood levels of the antibiotic.

One of the objects of this invention is to con-' tinuously maintaintherapeutic blood levels of 2 penicillin in humans and in animals forconsiderable periods of time.

Another object of the invention is to prevent the customary rapidelimination and destruction in vivo of penicillin. One of the objects ofthe invention is to obtain the maximum therapeutic eifect per unit ofpenicillin administered.

It is also an object of this invention to obtain more constant bloodlevels of penicillin.

A further object of the invention is to provide repository compositionscontaining penicillin which are stable and which are easy to administer.

Still another obj ect of this invention is to provide repositorycompositions containing pencillin which do not cause undesirablephysiological reactions on administration to humans or animals.

I have found that by intramuscular injection of a suspension of apenicillin salt in a vehicle comprising a, natural oil containing asmall amount of an organic compound possessing vasoconstrictorproperties that it is possible to continuously maintain therapeuticblood levels of penicillin over a long period of time. I have also foundthat this period of time when using my new preparations is several timesgreater than obtained when one injects a saline solution of avasoconstrictor and a penicillin salt or an oil or oil-wax suspension'ofa penicillin salt not containing any vasoconstrictor. By the practice ofmy invention I have found that more constant blood levels of penicillinare obtainable. This insures the presence of adequate amounts ofpenicillin for the exercise of a continuous therapeutic eiiect betweeninjections. The penicillin' compositions of the present invention arestable and do not cause undesirable physiological reactionsonadministration to humans or 40 zene and the like. I have found that onlyvery small amounts of .the vasoconstrictor need be 3 used in my newpreparations to accomplish the desired repository efiect. For example,in my oil suspension preparations, as little as 0.00005 g. ofepinephrine per ml. of the preparation is sufficient to enhance therepository action to a very marked degree. However, as high as 0.002 g.of epinephrine per ml. may be used without causing significant rise inblood pressure, although for a margin of safety and to prevent a nervousor restless feeling, it is preferable to use less than about 0.001 g.per ml.

By small amounts of vasoconstrictors as used herein and in the appendedclaims. I intend to. include those proportions of vasoconstrictors whichcan be used with a therapeutic dosage of penicillin to produce effectiveprolonged vasoconstriction without the undesirable nervous reactionswhich result when too much of the. vaseconstrictor is used. The limitsof these proportions will vary somewhat but are readily determined bysimple experiment. v

In the preparation of my new products I may use any bland,non-irritating natural oil such as peanut oil, sesame oil, cottonseedoil, castor oil,

corn oil, olive oil, rape seed oil, coconut oil and the like. I have.found that particularly valuable products are obtained when such naturaloils. also contain a small amount. of. dissolved wax such, as beeswax,spermaceti and similar waxes. These latter mixtures when incorporatedwith a. vaseconstrictor and. used as. vehicles ior penicillin saltsprolong the action of. penicillin. considerably more than similarcompositions not containing; wax.

The therapeutic blood level. of penicillin concentration in humans isbetween 0.02 and 0.03 Oxford units perml. or blood. serum. The main;

tenance of this therapeutic blood. level of.

cillin in humans is indicated by urinary excretion of over about 1000.Oxiord units. of penicillin per hour.

In accordance with the. present invention one to one and a half timesthe. therapeutic blood levels of penicillin may be maintained for atleast twelvehours. by a single. intramuscular injectionof as little as100,000- Oxford units at penicillin. The invention therefore makes itssibl to, treat in.- fections and diseases which yield to penicillintherapy by not more than two intramuscular injections of penicillin pertwenty-four hours in contrast to. the customary eight. to twelveintramuscular iniections. required. when penicillin salts in aqueous, orin saline solutions.

The invention is. illustrated by the following examples. EXAMPLE la 3ml. of refined peanut oil and 215 mg. of epinephrine are added to500,000 Oxford units of calcium penicillin contained in a small glassbottle. Two or three sterile glass beads are added,

the mixture warmedto about C1, the bottlest-opperedand shaken for tenminutes to insure dispersion of the particles of penicillin. The mixtureis then diluted to 5 ml. with refined peanut oil and shaken toinsurehomogeneity.

This therapeutic preparation is uniform suspension of calcium penicillinwhich is stable and suitable for intramuscular injection into humans oranimals. Injection of 1 ml. of this product furnishes 100,000 Oxfordunits of calcium penicillin the action of which is continuously:maintained above the therapeutic level for about 12 hours.

EXAMPLE. 2.

4.0 ml. of warm (about 40 C.) refined peanut 1 Oxford units of drycalcium penicillin contained in a small glass bottle. The bottle isstoppered and shaken to disperse the penicillin salt. The mixture isthen diluted to 5 ml. with refined peanut oil.

This therapeutic preparation is stable and contains 200,000 Oxford unitsof calcium penicillin per ml. 0n intramuscular injection of thispreparation into humans or animals the therapeutic blood level ofpenicillin is maintained for at least twelve hours.

Table I shows representative blood levels obtained following theintramuscular injection of the penicillin preparation prepared asdescribed in, this Example.

Table I Penicillin blood concentration at the end of hours in OxfordUnits per ml.

Patient No. serum 1 I 6 ours. 8.5 hours. labours. 12 hours Determined.by themediliedmethod ct Boseuhlati as. desc ibed in J". Beet, 48, 5991944 Extracts 3 3 m1. of warm (about 35- C.) refined peanut oil and 0.5mg. of epinephrine are added to 500,000 Oxford units of calciumpenicillin contained in a small glass bottle. The bottle is stoppered,shaken well to disperse the penicillin salt and then the mixture dilutedto 5 ml. with refined peanut oil.

This therapeutic preparation is stable and contains 100,000 Oxford unitsof calcium penicillin per ml. When 1 ml. of this preparation is injectedintramuscularly into humans the efiect of the penicillin maintainedseveral times as long as in similar preparations not containingepinephrine.

' EXAMPLE 4 31111. of refined peanut oil and 2.5. mg. of neosynephrineare added to 500,000 Oxford units of calcium penicillin contained in asmall glass bottle. Two or three sterile lass beads are added, themixture warmed to about. 40 (2., the bottle stoppered and shaken for tenminutes to insure dispersion of the particles of penicil in. The mixtureis then. diluted to 5. ml. with refined peanut oil and shaken to insurehomo enei y.

This. therapeutic preparation is a uniform suspension of. calciumpenicillin which is stable and suitablev for intramuscular injectioninto humans or animals. Injection of 1 m1. of this product furnishes100,000 Oxford units. of calcium penicillin the action of which iscontinuously maintained above the therapeutic level for about 12 hours.

EXAMPLES 3 ml. of warm (about; 40 C.) refined peanut oil and 1.25 mg. ofneosynephrine are added to 500,000 Oxford units of calcium penicillincontained in a small glass bottle. The bottle is stoppered, the mixtureagitated, to disperse the Denioil and 1 mg. of epinephrine are added to1,000,000- cillin salt and the mixture diluted to a volume of 5 ml. withrefined peanut oil and the mixture shaken to insure homogeneity.

This stable preparation contains 100,000 Oxford units of calciumpenicillin per ml. and when injected into human subjects maintainstherapeutic blood levels of penicillin over much longer periods of timethan similar preparations not containing a vasoconstrictor drug.

EXAMPLE 6 3 ml. of warm (about 40 C.) peanut oil and 1.2 mg. of2-naphthylmethylimidazoline are added to 300,000 Oxford units of calciumpenicillin contained in a small glass bottle. The bottle is stoppered,shaken well to disperse the penicillin salt and diluted to a volume of 4ml. with refined peanut oil.

This stable preparation contains 15,000 Oxford units of calciumpenicillin and when administered by the intramuscular route to humansubjects maintains a therapeutic blood level of penicillin for a muchlonger period of time than a similar preparation not containing thevasoconstrictor drug.

EXAMPLE 7 3 ml. of refined peanut oil and 2.5 mg. of epinephrine areadded to 500,000 Oxford units of sodium penicillin contained in a smallglass bottle. Two or three sterile glass beads are added, the mixturewarmed to about 40 C., the bottle stoppered and shaken for ten minutesto insure dispersion of the particles of penicillin. The mixture is thendiluted to 5 ml. with refined peanut oil and shaken to insurehomogeneity.

This therapeutic preparation is uniform suspension of sodium penicillinwhich is stable and suitable for intramuscular injection into humans oranimals. Injection of 1 ml. of this product furnishes 100,000 Oxfordunits of sodium penicillin the action of which is continuouslymaintained above the therapeutic level for about 12 hours.

EXAMPLE 8 3 ml. of refined peanut oil and 2.5 mg. of neosynephrine areadded to 500,000 Oxford units of sodium penicillin contained in a smallglass bottle. Two or three sterile glass beads areadded, the mixturewarmed to about 40 C., the bottle stoppered and shaken for ten minutesto insure dispersion of the particles of penicillin. The mixture is thendiluted to 5 ml. with refined peanut oil and shaken to insurehomogeneity.

This therapeutic preparation is a uniform suspension of sodiumpenicillin which is stable and suitable for intramuscular injection intohumans or animals. Injection of 1 ml. of this product furnishes 100,000Oxford units of sodium penicillin the action of which is continuouslymaintained above the therapeutic level for about 12 hours.

EXAMPLE 9 2.5 mg. of epinephrine and 3 ml. of warm (about 40 C.) refinedpeanut oil containing 3% by weight of dissolved beeswax are added to500,000 Oxford units of calcium penicillin contained in a small glassbottle. The bottle is stoppered and shaken Well to disperse thepenicillin salt. The mixture is diluted to a volume of 5 ml. with warmrefined peanut oil containing 3% by weight of dissolved beeswax andshaken again to insure homogeneity.

This stable therapeutic preparation contains 100,000 Oxford units ofcalcium penicillin per ml. Therapeutic blood levels of penicillin are1main- 2.5 mg. of 2-naphthylmethylimidazoline and 3 m1. of warm (about45 C.) refined peanut oil containing 3% dissolved beeswax are added to500,000 Oxford units of calcium penicillin contained in a small glassbottle. Two or three sterile glass beads are added and the mixtureshaken for five minutes. The mixture is made up to a volume of 5 ml.with warm refined peanut oil containing 3% beeswax.

When 1 ml. of this stable composition which contains 100,000 Oxfordunits of calcium penicillin per ml. is injected intramuscularly intohuman subjects therapeutic blood levels of penicillin are maintained forat least twelve hours.

EXAMPLE 1 l 3 ml. of warm cottonseed oil and 2.5 g. ofl-ahydroxy-b-methylamino-4-hydroxyethylbenzene are added to 500,000Oxford units of calcium penicillin contained in a small glass bottle.The bottle is stoppered and the mixture shaken to disperse thepenicillin salt. The mixture is diluted to a volume of 5 ml. withcottonseed oil and mixed well.

This stable therapeutic product contains 100,- 000 Oxford units ofcalcium penicillin per ml. and

when administered to humans in dosages of 100,-

000 Oxford units gives therapeutic blood levels of penicillin for aperiod of about twelve hours.

EXAMPLE 12 2 ml. of Warm coconut oil and 0.9 mg. of epinephrine areadded to 300,000 Oxford units of calmuch larger period of time thansimilar preparation not containing epinephrine.

EXAMPLE 13' A mixture consisting of 1 mg. of epinephrine and 8 ml. ofwarm refined corn oil is added to 500,000 Oxford units of calciumpenicillin contained in a small glass bottle. The bottle is stoppered,the mixture shaken to disperse the penicilllin salt and the preparationdiluted to a volume '7 of 10 ml. with refined corn oil.

This preparation is stable and contains 50,000 Oxford units of calciumpenicillin per 1011.. When this product is administered intramuscularlyto humans therapeutic blood levels of penicillin are maintained over amuch longer period of time than by administration of the same quantityof similar preparation not containing epinephrine.

EXAMPLE 14 2.5 mg. of epinephrine and 4 ml. of warm sesame oil are addedto 500,000 Oxford unitsof calcium penicillin contained in a small glassbottle. The bottle is stoppered, shaken to disperse the penicillin saltand the mixture diluted to a volume of 5 ml. with sesame oil.

This preparation which contains 100,000 Oxfor units of calciumpenicillin is stable and when injected intramuscularly into humansresults in therapeutic blood levels over much longer periods of timethan corresponding preparation not containing epinephrine.

1 The great superiority of .the penicillin preparations of the presentinvention over the known penicillin preparations is readily apparentfrom examination of Table II which shows the rapid urinary excretion ofpenicillin in human patients prising a suspension of a penicillin saltin a nonaqueous vehicle comprising an injectable natural oil containinga small amount of an organic compound possessing vasoconstrictorproperties, said composition, upon injection, providing prolongedtollowms intramuscular injec ions of 1 m of therapeutic blood levels ofpenicillin as comvarious control preparations of penicillin known paredwith the blood levels attainable upon ino the prw a t as omp ed to themore p ojection of similar compositions containing no o ed urinaryexcretion of my ne preparations. vasoconstrictor and with the bloodlevels attain- Table II- Oxford Units oi.Penlcillin Excreted at Y rTotal per- Patient Formula W m 2 0091 P9 11 W 1 cent. B No. cillinaliou'rs hours 7hours 0hours 2-ihours Excreted Control Prcpn. #L 450,000 Units of sodium penicillin in water 57,600 5,000 7 0 0 0 62Control Prepn. #2. 2 50,000 linit s of sodium penicillin-{05 mg,epinephrine 36,400 5, 000 700 0 0 42 Cntrol Prepn. #3. 18 100,000 Unitsof calcium penicillin in peanut oil 32, 500 1,150 0 0 0 33.7 5 0 0 9 99.V. 9 4&5 Preps. described a 100,000 Units of calcium penicillin+0.5 mg.epi- 24,100 14,800 12,000 5,400 5,000 02 in Example 1. nephrine inpeanut oil.

7 28, 500 18,000 13,000 5, 300 2,600 07 12 37, 240 24, 000 0, 300 7,0001,700 77 p 1a V V V 22,750 29,300 6,000 315 58 Prepn. described 30100,000 Units of calcium penicillin-P01 mg. epi- 21,000 5,500 1,000 5000 27.5

in Example 3. nephrine lIl peanut 011. I

M V c. H @300 5,300 12,000 2,000 ,200 14 Control Prepn. #4- 14 100,000gnilts of calcium penicillin+3% beeswax in 3, 500 5,200 1,250 250 250Prepn. described 1 100,000 Units of calcium penicillin-+0.5 m em.- 1,0300, 0 0,4 0 a 13,400

in Example 9. nephrine+3% beeswax in peanut oil.

1 Oxfordllnits of penicillin determined by the Oxford. Plate Testasdescrihcd by Fleming.

2 cc. of this preparation administered, a total of 100,000 Oxford Units5 Samples not collected.

The penicillin products of the present invention when administered tohumans or animals by the intramuscular route give blood levels which induration, continuity and intensity are similar to those shown in Table Iabove for the specific preparation described in Example 2.

The penicillin suspensions of the invention are more easily prepared bywarming the vehicle to enhance its fluidity. However, I have found thatin many cases it is not necessary to first warm the vehicle to obtain ahomogeneous suspension of the penicillin salt. 7

While in the above examples I have used the free bases of thevasoconstrictors it should be understood that I may also use anynon-toxic acid addition salt of these compounds in the preparation of mynew therapeutic products. I have found that little or no reaction takesplace between these acid addition salts of the vasoconstricter and thepenicillin salts when they are suspended in the oil media of the presentinvention. Some specific examples of the nontoxic acid addition salts ofthe vasoconstrictors which I may use are the hydrochloride, sulfate,phosphate, nitrate, acetate, citrate and tartrate salts.

Any non-toxic salt of penicillin may be used in the preparation of thepenicillin products herein described. For example, some of thepenicillin salts which I may use instead of the calcium and sodium saltsshown in the above examples are the ammonium, potassium, lithium andmagnesium salts of penicillin.

While suspensions of the present invention slowly settle out, I havefound that they do not pack and that they may be immediately anduniformly resuspendecl with ease.

What I claim is: I

1. An injectable therapeutic composition comable upon injection ofsimilar compositions containing no oil.

2. An injectable therapeutic composition comprising a suspension of apenicillin salt in a nonaqueous vehicle comprising an injectable naturaloil containing a small amount of epinephrine, said composition, uponinjection, providing prolonged therapeutio blood levels of penicillin ascompared with the blood levels attainable upon injection of similarcompositions containing no vasoconstrictor and with the blood levelsattainable upon injection of similar compositions containing no oil.

3. An lnjectable therapeutic composition consisting of a suspension ofcalcium penicillin in a non-aqueous vehicle comprising peanut oilcontaining a small amount of epinephrine, said composition, uponinjection, providing prolonged therapeutic blood levels of penicillin ascompared with the blood levels attainable upon injection of similarcompositions containing no vasoconstrictor and with the blood levelsattainable upon injection of similar compositions containing no oil.

4. An injectable therapeutic composition comprising a suspension ofcalcium penicillin in a non-aqueous vehicle comprising an injectablenatural oil containing a small amount of an organic compound possessingvasoconstrictor properties, said composition, upon injection, providingprolonged therapeutic blood levels of penicillin as compared with theblood levels attainable upon injection of similar compositionscontaining no vasoconstrictor and with the blood levels attainable uponinjection of similar compositions containing no oil.

5. An injectable therapeutic composition comprising a. suspension ofsodium penicillin in a non-aqueous vehicle comprising an injectablenatural oil containing a small amount of an organic compound possessingvasoconstrictor properties, said composition, upon injection, providingprolonged therapeutic blood levels of penicillin as compared with theblood levels attainable upon injection of similar compositionscontaining no vasoconstrictor and with the blood levels attainable uponinjection of similar compositions containing no oil.

6. An injectable therapeutic composition comprising a suspension ofsodium penicillin in a nonaqueous vehicle comprising peanut oilcontaining a small amount of epinephrine, said composition, uponinjection, providing prolonged therapeutic blood levels of penicillin ascompared with the blood levels attainable upon injection of similarcompositions containing no vasoconstrictor and with the blood levelsattainable upon injection of similar compositions containing no oil.

STEPHEN B. BINKLEY.

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